Halogenated benzamide derivatives

ABSTRACT

A method of treating viral infections by the administration of a halogenated benzamide derivative according to formula (III): in which R 1  is a halogen atom, and R 2 -R 6  are independently hydrogen, hydroxyl, C 1 -C 4  alkyl, —C 1 -C 4  alkoxy, acyloxy, nitro, halogen, —C(O)R 7  where R 7  is —C 1 -C 4  alkyl, or, aromatic including salts and hydrates of these compounds.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a divisional of application Ser. No. 11/221,256filed Sep. 6, 2005, now U.S. Pat. No. 7,285,567, which claims benefit toU.S. Provisional Application Ser. No. 60/608,354 filed Sep. 9, 2004. Theentire content of each above-mentioned application is herebyincorporated by reference in entirety.

FIELD OF THE INVENTION

The invention relates to halogenated benzamide derivatives, and morespecifically, benzamide derivatives characterized by greater specificityfor viral pathogens and less disruptive to beneficial gut microflora.

BACKGROUND OF THE INVENTION

Laser (2-(acetolyloxy)-N-(5-nitro-2-thiazolyl)benzamide, the compound offormula (I), also referred to as nitrothiazole, nitazoxanide, or NTZ, isknown for use in the treatment and prevention of parasitic infections,bacterial infections, fungal infections, diarrhea and other intestinaltroubles (U.S. Pat. Nos. 3,950,351, 4,315,018 and 5,578,621) includingtreatment of trematodes (U.S. Pat. No. 5,856,348). The preparation ofNTZ is disclosed in U.S. Pat. No. 3,950,351. Improved pharmaceuticalcompositions for delivery of NTZ are disclosed U.S. Pat. Nos. 6,117,894and 5,968,961.

It has been postulated that, in anaerobic bacteria and protozoa, NTZexhibits a mode of action based upon reduction of its nitro group bynitroreductases, and particularly pyruvate ferredoxin oxidoreductase(PFOR) dependent electron transfer reactions that are essential foranaerobic energy metabolism. Nothing is currently known regarding thepossible mode of action of NTZ for helminthes, however, the enzymes ofanaerobic electron transport are considered as potential targets, withthe 5-nitro group implicated in this mechanism.

Compounds according to formula (II), in which one of R₁₋₅ is —OH and theremainder of R₁₋₅ being H, are known to exhibit antiviral activity, andare known for treatment of human viral diseases such as those caused byhuman cytomegalovirus, varicella zoster, Epstein Barr virus, HSV-I andHSV-II (U.S. Pat. Nos. 5,886,013 and 6,020,353).

While potent, these compounds are not selective for only viralpathogens. They are described as having excellent efficacy againstparasites, bacteria and fungus. In practice, this is associated with aproblem. Namely, in humans and many animals, the gut contains beneficialpopulations of microflora, principally comprised of anaerobic bacteria.Oral administration of broad spectrum compounds such as those of Formula(II) kills the bacterial gut flora, which may lead to secondarycomplications including diarrhea requiring further treatment.

Accordingly, there is a need for therapeutic compounds that are moreselective for viral pathogens. Most preferably, these compounds shouldpossess antiviral activity, but be substantially devoid of antibacterialand antiparasite activity, at least to the extent of avoidingdeleterious effects upon the beneficial gut microflora when administeredorally.

This need, and more, is achieved by the present invention, as willbecome clear to one of ordinary skill upon reading the followingdisclosure and examples.

SUMMARY OF THE INVENTION

The present invention relates to antiviral benzamide derivatives thatare more selective for viral pathogens, and accordingly cause reduceddeleterious effects upon beneficial gut microflora when administeredorally.

In a first aspect, the invention is surprisingly made by replacing thenitro substituent, which has until now been believed to be the key tothe activity of NTZ, with a halogen atom. This substitution may be madein any of the known therapeutically effective2-benzamido-5-nitro-thizaoles (wherein the benzene ring may be variouslysubstituted). Surprisingly, the novel halogenated compounds retain theirantiviral properties, but they lack activity against the bacterial gutmicroflora when administered orally.

Examples of these known 2-benzamido-5-nitro-thizaoles, which areanalogues of the compounds of the present invention differing only inthat in accordance with the present invention the nitro group is removedand replaced with a halogen atom, are extensively set forth in the abovereferenced U.S. patents, and U.S. Pat. No. 5,886,013 in particular,their disclosure being incorporated herein by reference.

The present invention further provides (5-halo-2-thiazolyl)benzamidecompounds according to formula (III):

in which

R₁ is a halogen atom, preferably F, Cl, Br, or I, more preferably Br orCl, most preferably Br, and

R₂-R₆ are independently hydrogen, hydroxyl, C₁-C₄ alkyl, —C₁-C₄ alkoxy,acyloxy (preferably acetoxy or propionoxy), nitro, halogen, —C(O)R₇where R₇ is —C₁-C₄ alkyl, or, aromatic (preferably unsubstituted orsubstituted phenyl or benzyl), including salts and hydrates of thesecompounds.

Preferably, one of R₂-R₆ is hydroxyl.

Preferably at least one of R₂-R₆ are other than hydrogen, and morepreferably at least two of R₂-R₆ are other than hydrogen.

Two adjacent R₂-R₆ may together form a benzyl ring.

Preferably, R₂-R₆ include no more than one acyloxy and no more than onehalogen.

The present invention further provides antiviral compounds according toformula (IV):

in which R₁ is a halogen atom, R₈ is —C(O)R₁₀, where R₁₀ is —C₁-C₄alkyl, and R₉ is —C₁-C₄ allyl or —C₁-C₄ alkoxy, including salts andhydrates of these compounds.

The invention further provides antiviral pharmaceutical compositionscomprising a compound of Formula (III) or (IV) and a pharmaceuticallyacceptable carrier.

Finally, the invention provides a method of treating or preventing aviral infection in an animal or human subject, the method comprisingadministering to said subject at least one dose of the pharmaceuticalcomposition comprising an effective amount of the antiviral compoundaccording to Formula (III) or (IV) and a pharmaceutically acceptablecarrier.

DETAILED DESCRIPTION

In Compounds of the present invention include those according to formula(III):

in which

R₁ is a halogen atom, preferably F, Cl, Br, or I, more preferably Br orCl, most preferably Br, and

R₂-R₆ are independently hydrogen, hydroxyl, C₁-C₄ alkyl, —C₁-C₄ alkoxy,acyloxy (preferably acetoxy or propionoxy), nitro, halogen, —C(O)R₇where R₇ is —C₁-C₄ alkyl, or, aromatic (preferably phenyl or benzyl,which may be further substituted), including salts and hydrates of thesecompounds.

Preferably, one of R₂-R₆ is hydroxyl.

Preferably at least one of R₂-R₆ are other than hydrogen, and morepreferably at least two of R₂-R₆ are other than hydrogen.

Two adjacent R₂-R₆ may together form a benzyl ring.

Preferably, R₂-R₆ include no more than one acyloxy and no more than onehalogen. Compounds according to the present invention are illustrated bythe following non-limiting list:

Code Molecular Molecular Number Structure Weight Formula RM-4803

355.21 C₁₃H₁₁BrN₂O₃S RM-4804

310.75 C₁₃H₁₁ClN₂O₃S RM-4806

371.21 C₁₃H₁₁BrN₂O₄S RM-4819

313.17 C₁₁H₉BrN₂O₂S RM-4820

341.18 C₁₂H₉BrN₂O₃S RM-4821

355.21 C₁₃H₁₁BrN₂O₃S RM-4822

355.21 C₁₃H₁₁BrN₂O₃S RM-4826

313.17 C₁₁H₉BrN₂O₂S RM-4827

333.59 C₁₀H₆BrClN₂O₂S RM-4831

317.13 C₁₀H₆BrFN₂O₂S RM-4832

299.14 C₁₀H₇BrN₂O₂S RM-4833

329.17 C₁₁H₉BrN₂O₃S RM-4834

329.17 C₁₁H₉BrN₂O₃S RM-4835

284.72 C₁₁H₉ClN₂O₃S RM-4836

284.72 C₁₁H₉ClN₂O₃S RM-4838

333.59 C₁₀H₆BrClN₂O₂S RM-4839

333.59 C₁₀H₆BrClN₂O₂S RM-4840

378.04 C₁₀ H₆Br₂N₂O₂S

Preferred examples of compounds within Formula (III) include:

-   2-(acetolyloxy)-3-methyl-N-(5-bromo-2-thiazolyl)benzamide (RM4803);-   2-(hydroxy)-3-methyl-N-(5-bromo-2-thiazolyl)benzamide (RM4819);-   2-(acetolyloxy)-N-(5-bromo-2-thiazolyl)benzamide (RM4820);-   2-(acetolyloxy)-5-methoxy-N-(5-bromo-2-thiazolyl)benzamide (RM4821);    and-   2-(acetolyloxy)-5-methoxy-N-(5-bromo-2-thiazolyl)benzamide (RM4822).

It has further been discovered that compounds with a hydroxylsubstitutent in the ortho position of the benzene ring have goodefficacy. Thus, from among the above illustrative compounds, thefollowing compounds are preferred: RM-4819, RM-4826, RM-4827, RM-4831,RM-4832, RM-4833, RM-4834, RM-4835, RM-4836, RM-4838, RM-4839, RM-4840.

Compounds according to the invention preferably include those of formula(IV):

wherein:

R₁ is halogen, preferably F, Cl, Br, or I, more preferably Br or Cl,most preferably Br,

R₈ is —C(O)R₁₀, in which R₁₀ is —C₁-C₄ alkyl. R₁₀ includes methyl,ethyl, propyl and butyl, including isomers thereof. Methyl is preferred,whereby the benzamide substituent is acetolyloxy, and

R₉ is —C₁-C₄ alkyl or —C₁-C₄ alkoxy. Methyl and methoxy are preferred.Methyl is most preferred.

Examples of compounds within Formula (IV) include:

-   2-(acetolyloxy)-3-methyl-N-(5-bromo-2-thiazolyl)benzamide (RM4803);-   2-(acetolyloxy)-3-methyl-N-(5-chloro-2-thiazolyl)benzamide (RM4804);    and-   2-(acetolyloxy)-3-methoxy-N-(5-bromo-2-thiazolyl)benzamide (RM4806).

The compositions of the present invention may be formulated as solid orliquid dosage forms, or as pastes or ointments, and may optionallycontain further active ingredients.

The pharmaceutical compositions of the present invention comprise apharmaceutically acceptable carrier, which is not particularly limited,and includes a wide range of carriers known to those of ordinary skillin the art, and including wetting or dispersing agents (U.S. Pat. No.5,578,621), starch derivatives (U.S. Pat. No. 5,578,621), excipients,and the like. Tablet embodiments may optionally comprise a coating of asubstance that constitutes an enteric coating, i.e. a coating thatsubstantially insoluble in gastric secretion but substantially solublein intestinal fluids.

Pharmaceutical compositions comprising compounds according to Formula(III) or (IV) are preferably formulated for oral administration and areoptionally in the form of a liquid, for example an emulsion or asolution or a suspension in water or oil such as arachis oil, or otherliquid. Formulations of non-aqueous micellar solutions may be preparedaccording to the method disclosed in U.S. Pat. No. 5,169,846.Alternatively, tablets can be manufactured, for example, by performingthe following steps: wet granulation; drying; and compression. Filmcoating is generally performed with organic solvents.

The term “selective antiviral” as used herein means that, at dosageseffective for the prevention or treatment of a viral disease, theactivity is more antiviral than antibacterial, antifungal, orantiparasite, and gut flora of the subject is not disrupted to levelsexpected with broad spectrum antibiotics.

The preferred antiviral treatment or prophylactic dosages of thecompounds of the present invention may depend upon the weight of thesubject, and may be inferred by one of ordinary skill without undueexperimentation by reference to the following examples, which are setforth for purposes of illustration and are not intended to be limiting.

EXAMPLE 1 Testing Against Viruses

Methods

Non-Hepatic Viruses

Cell cultures and Treatments. HEp-2 laryngeal carcinoma cells, monkeykidney 37RC, MA104 and VERO cells, canine Madin-Darby kidney (MDCK) andmammary adenocarcinoma (A72) cells, were grown at 37° C. in a 5% CO₂atmosphere in RPMI medium (Gibco-Invitrogen, Carlsbad, Calif.),supplemented with 10% fetal calf serum (FCS), 2 mM glutamine andantibiotics. Compounds dissolved in DMSO stock solution (50 mg/ml) werediluted in culture medium and added to infected cells immediately afterthe 1 hour adsorption period. Compounds were maintained in the mediumfor the duration of the experiment. Controls received equal amounts ofDMSO diluent. Each concentration of each compound was tested induplicate and each experiment was repeated twice.

Virus infection and titration. The following viruses were utilized:Influenza A: strain Puertorico (PR8); Paramyxovirus (Parainfluenza):Sendai virus (SV); Rhabdovirus: Vesicular Stomatitis Virus (VSV);Rotavirus: Simian Rotavirus SA-11 (SA-11); Herpes Simplex virus type 1:strain F1 (HSV-1); Coronavirus: canine coronavirus strain S-378 (CCoV).Confluent cell monolayers were infected with Influenza A virus (MDCKcells) or parainfluenza SV (37RC cells) for 1 h at 37° C. at amultiplicity of infection (m.o.i.) of 5 HAU (HemagglutinatingUnits)/10.sup.5 cells. Alternatively, confluent cell monolayers wereinfected with HSV-1 (HEp-2 cells), VSV (MA104 cells), CCoV (A72 cells)or Rotavirus SA-11 (MA104 cells) for 1 h at 37° C. at a m.o.i. of 5 PFU(Plaque Forming Units)/10⁵ cells for HSV-1, VSV and CCoV and 1 PFU/10⁵cells for SA-11. After the adsorption period, the viral inoculum wasremoved and cell monolayers were washed three times withphosphate-buffer saline (PBS). Cells were maintained at 37° C. inappropriate culture medium containing 2% FCS in the presence of the testcompound or control diluent. Virus yield was determined 24 hours postinfection (p.i.) by hemagglutinin titration (WSN, PR8, SV and SA-11) orCPE50% assay (VSV, HSV-1, and CCoV), according to standard procedures(Amici, C., Belardo, G., Rossi, A. & Santoro, M. G. Activation of IκBkinase by Herpes Simplex virus type 1. A novel target for anti-herpetictherapy. J. Biol. Chem. 276, 28759-28766 (2001) and Bernasconi, D.,Amici, C., La Frazia, S., Ianaro, A. & Santoro, M. G. The IκB kinase isa key factor in triggering Influenza A virus—induced inflammatorycytochine production in airway epithelial cells. J. Biol. Chem. 280,24127-24134 (2005)).

Cell toxicity. Cell viability was determined by the3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) toMTT formazan conversion assay (Sigma-Aldrich, St Louis, Mo.). For MTTassay, reduced MTT (formazan) was extracted from cells by adding 100.mu.l of acidic isopropanol containing 10% Triton X-100, and formazanabsorbance was measured in an ELISA microplate reader at two differentwavelengths (540 and 690 nm).

Hepatitis B Virus

Anti-Hepatitis B Virus (HBV) analyses and an assessment of cytotoxicitywere performed in a 9-day assay in the chronically-producing HBV humanhepatoblastoma cell line, 2.2.15, as previously described (Korba, B. E.& Gerin, J. L. Use of a standardized cell culture assay to assessactivities of nucleosides analogues against hepatitis B virusreplication. Antivir. Res. 19, 55-70 (1992)).

Hepatitis C Virus

Anti-Hepatitis C Virus (HCV) analyses and an assessment of cytotoxicitywere performed in a 3-day assay in the HCV replicon-containing humanhepatoblastoma cell line, AVA5 (Okuse, C., Rinaudo, J. A., Farrar, K.,Wells, F. & Korba, B. E. Enhancement of antiviral activity againsthepatitis C virus in vitro by interferon combination therapy. Antivir.Res. 65, 23-34 (2005)) as previously described (Blight, K. J.,Kolykhalov, A. A. & Rice, C. M. Efficient initiation of HCV RNAreplication in cell culture. Science 290, 1972-1974 (2000)).

Results of Testing Against Viruses

TABLE 1 Activity of RM-4803 and RM-4819 against viruses in cell culture.EC₅₀ (μM)/SI Virus RM4819 RM4803 Cell Culture Rotavirus: Simianrotavirus 0.3/>500  0.06/>2500 MA104 SA-11 Influenza A: PR8 strain9.6/>17  2.8/>50 MDCK Paramyxovirus: Sendai virus 1.3/>125  1.1/>12537RC Coronavirus: canine 4.9/>33  4.2/13   A72 coronavirus strain S-378Rhabdovirus: Vesicular 1.6/>100 2.8/>50 MA104 stomatitis virus HerpesSimplex type 1: 0.6/>250  5.6/3    HEp-2 strain F1 EC₅₀ = drugconcentration at which a 2-fold depression of viral DNA or RNA (relativeto the average levels in untreated cultures) was observed. CC₅₀ = drugconcentration at which a 2-fold depression of reduced MTT was observedrelative to average levels in untreated cultures. SI (selectivity index)= CC₅₀/EC₅₀.

TABLE 2 Activity of other compounds against paramyxovirus: sendai virusin cell culture. Paramyxovirus: Sendai virus Compound EC₅₀ (μM) SIRM-4820 0.34 35 RM-4821 0.36 >50 RM-4822 0.36 7 EC₅₀ = drugconcentration at which a 2-fold depression of viral RNA (relative to theaverage levels in untreated cultures) was observed. CC₅₀ = drugconcentration at which a 2-fold depression of reduced MTT was observedrelative to average levels in untreated cultures. SI (selectivity index)= CC₅₀/EC₅₀.

TABLE 3 Activity of compounds against HBV replication in 2.2.15 cellculture. Extracellular Intracellular Selectivity Virion DNA HBV R.I.Index Compound EC₅₀(μM) EC₉₀(μM) EC₅₀(μM) EC₉₀(μM) CC₅₀(μM) Virion R.I.Lamivudine 0.058 ± 0.006  0.164 ± 0.015  0.172 ± 0.020 0.660 ± 0.068 2229 ± 76 12959 3377 RM4803 6.3 ± 0.7   15 ± 1.1   12 ± 1.5 50 ± 5.5>1000^(§) >67 >20 RM4819 3.5 ± 0.5  9.0 ± 0.8  7.6 ± 0.9 22 ± 2.6>1000^(§) >111 >46 ^(§)No significant cytotoxic effects were observed upto the highest indicated concentration.

Values presented (±standard deviations [S.D.]) were calculated by linearregression analysis using data combined from all treated cultures. S.D.were calculated using the standard error of regression generated fromlinear regression analyses (QuattroPro.™.). EC₅₀, EC₉₀32 drugconcentration at which a 2-fold, or a 10-fold depression of HBV DNA(relative to the average levels in untreated cultures), respectively,was observed, CC₅₀=drug concentration at which a 2-fold depression ofneutral red dye uptake (relative to the average levels in untreatedcultures) was observed, The EC₉₀ values were used for the calculation ofthe Selectivity Indexes [S.I.] since at least a 3-fold depression of HBVlevels is typically required to achieve statistical significance in thisassay system. HBV R.I.=intracellular HBV DNA replication intermediate.

TABLE 4 Activity of compounds against hepatitis C virus replication inAVA5 cell culture. Selectivity Compound CC₅₀ (μM) EC₅₀ (μM) EC₉₀ (μM)Index ∝ - >10,000*^(§)  2.2 ± 0.2*    8. ± 0.6* >4,545 InterferonRibavirin   61 ± 2.9 94 ± 10 >100^(§) 0.6 RM4803 282 ± 21  37 ± 2.7 98 ±9.3 7.6 RM4819 164 ± 18 8.9 ± 0.7 79 ± 8.2 18 *Values for interferon areexpressed as “IU/ml.” ^(§)No significant cytotoxic or antiviral effectswere observed up to the highest indicated concentration.

Values presented (±standard deviations [S.D.]) were calculated by linearregression analysis using data combined from all treated cultures. S.D.were calculated using the standard error of regression generated fromthe linear regression analyses (QuattroPro.™.). EC₅₀, EC₉₀=drugconcentration at which a 2-fold, or a 10-fold depression of HCV RNA(relative to the average levels in untreated cultures), respectively,was observed. CC₅₀=drug concentration at which a 2-fold depression ofneutral red dye uptake was observed relative to the average levels inuntreated cultures. Selectivity index=CC₅₀/EC₅₀.

EXAMPLE 2 Testing Against Anaerobic Bacteria

Methods. Recent clinical anaerobic isolates (2000 to date) comprised 40B. fragilis group, 26 Prevotella/Porphyromonas, 28 fusobacteria, 16anaerobic Gram positive cocci, 14 anaerobic Gram-positivenon-sporeforming rods and 18 clostridia. CLSI agar dilution MICmethodology with enriched Brucella blood agar and inocula of1.times.10.sup.5 cfu/spot was used. Plates were incubated in ananaerobic glove box at 35° C. for 48 h.

Results. MIC₅₀/MIC₉₀ values (μg/ml) were as follows:

B. fragilis Gram + Gram + gp Prev/Porphy Fusobacteria cocci rodsClostridia All Drug (40) (26) (28) (16) (14) (18) (142) Nitazoxanide 2/44/8   1/4 0.5/2     16/>32  0.5/4 2/4   Tizoxanide 2/4  2/16 0.5/20.5/1      8/>32  0.25/2 2/4   RM 4803 >32/>32 >32/>32  >32/>32 >32/>32 >32/>32   >32/>32 >32/>32   RM 4819 >32/>32 >32/>32  >32/>32 >32/>32 >32/>32   >32/>32 >32/>32   Amoxicillin- 1/4 0.06/0.5 0.5/4 0.125/0.5  0.25/1.0   0.125/1.0 0.5/2.0   clavulanic acidClindamycin    2/>32  <0.015/<0.015   0.06/0.125 0.125/0.5  0.125/4       1/>32 0.125/8.0    Metronidazole 1/2 0.5/2     0.25/0.250.5/1.0 >16/>16 0.25/2 1.0/2.0  

Results showed that nitazoxanide, tizoxanide, potent against allanaerobic bacteria groups except for Gram-positive anaerobic rodsincluding lactobacilli (which are in reality mostly microaerophils). Bycontrast, RM 4803 and RM 4819 were without significant activity.

EXAMPLE 3 Antiviral Activity

Compounds within Formula (IV) of the present invention exhibit potentantiviral activity, as shown in Table 5.

Activity of RM-4803, RM-4804 and RM-4806 against viruses in cellmonolayer Human Rhinovirus Type 39 Influenza A Virus OH-Hela MDCK 2%McCoys + Hepes 0% EMEM + Buffer Hepes + Trypsin Microscopic MicroscopicCompound Spectrophotometer Spectrophotometer R₁ = Br 0.06 0.03 0.45 0.18R₂ = acetolyloxy R₃ = methyl (RM 4803) R₁ = Cl 0.57 0.32 0.93 0.57 R₂ =acetolyloxy R₃ = methyl (RM 4804) R₁ = Br 5.0 4.0 0.46 0.57 R₂ =acetolyloxy R₃ = methoxy (RM 4806) Pirodavir 0.007 0.004 NA NAOseltamivir NA NA 0.13-0.17 0.08-0.36

EC₅₀ (.mu.g/mL) values for2-(acetolyloxy)-3-methyl-N-(5-bromo-2-thiazolyl)benzamide (RM4803),2-(acetolyloxy)-3-methyl-N-(5-chloro-2-thiazolyl)benzamide (RM4804), and2-(acetolyloxy)-3-methoxy-N-(5-bromo-2-thiazolyl)benzamide (RM4806), onHuman Rhinovirus Type 39 (HRV-39), and H₃N₂ influenza virus, type A,using a multiple cycle CPE inhibition assay on OH-I Hela and Madin DarbyCanine Kidney (MDCK) cell monolayers, respectively, were measured bymicroscopic and spectrophotometric methods. Pirodavir and Oseltamivirwere included as positive controls.

EXAMPLE 4 Selective Anti-Viral Activity

The above identified compounds according to Formula (IV) were tested byconventional means against Trichomis vaginalis, Giardia Intestinalis,and Trypanosoma brucei.2-(acetolyloxy)-3-methyl-N-(5-bromo-2-thiazolyl)benzamide (RM4803),2-(acetolyloxy)-3-methyl-N-(5-chloro-2-thiazolyl)benzamide (RM4804), and2-(acetolyloxy)-3-methoxy-N-(5-bromo-2-thiazolyl)benzamide (RM4806) eachfailed to exhibit antiparasite activitity against Trichomonas vaginalis,Giardia intestinalis, or Trypanosoma brucei at concentrations of atleast 50 μg/mL.

Accordingly, it has been demonstrated that in accordance with thepresent invention, novel compounds can be provided which are generallycharacterized by selective antiviral activity.

As an additional benefit, it has been discovered that the abovehalogen-substituted benzamide compounds are effective againstintracellular protozoa including Cryptosporidium spp., Neospora spp. andSarcocystis neurona (RM-4820, RM-4821 and RM-4822).

With respect to the above description, it is to be realized that theoptimum formulations and methods of the invention are deemed readilyapparent and obvious to one skilled in the art, and all equivalentrelationships to those described in the specification are intended to beencompassed by the present invention.

Therefore, the foregoing is considered as illustrative only of theprinciples of the invention. Further, since numerous modifications andchanges will readily occur to those skilled in the art, it is notdesired to limit the invention to the exact construction and operationshown and described, and accordingly, all suitable modifications andequivalents may be resorted to, falling within the scope of theinvention.

Certain references, patents and other printed publications have beenreferred to herein: the teachings and scope of each of said publicationsare hereby incorporated in their respect entireties by reference.

Now that the invention has been described:

1. A method for treating viral infections, comprising administering to asubject in need of treatment an effective amount of a pharmaceuticalcomposition comprising as active agent a compound according to formula(III):

in which R₁ is a halogen atom, and R₂-R₆ are independently hydrogen,hydroxyl, C₁-C₄ alkyl, —C₁-C₄ alkoxy, acyloxy, nitro, halogen, —C(O)R₇where R₇ is —C₁-C₄ alkyl, or, aromatic including salts and hydrates ofthese compounds, wherein at least one of R₂-R₆ is other than hydrogen.2. A method for treating viral infections, comprising administering to asubject in need of treatment an effective amount of a pharmaceuticalcomposition comprising as active agent a compound according to formula(III):

wherein R₁ is a halogen atom, and R₂-R₆ are independently hydrogen,hydroxyl, C₁-C₄ alkyl, —C₁-C₄ alkoxy, acyloxy, —C(O)R₇ where R₇ is—C₁-C₄ alkyl, or, aromatic including salts and hydrates of thesecompounds, wherein at least one of R₂-R₆ is other than hydrogen.
 3. Amethod for treating viral infections, comprising administering to asubject in need of treatment an effective amount of a pharmaceuticalcomposition comprising as active agent a compound according to formula(III):

wherein is a halogen atom, R₂-R₆ are independently hydrogen, halogen,nitro, hydroxyl, C₁-C₄ alkyl, —C₁-C₄ alkoxy, acyloxy, —C(O)R₇ where R₇is —C₁-C₄ alkyl, or, aromatic including salts and hydrates of thesecompounds, wherein at least two of R₂-R₆ is other than hydrogen and atleast one of R₂-R₆ is hydroxyl or acyloxy.